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NSG mice are among the most immunodeficient mouse model being used in various scientific branches. In diabetelogical research diabetic NSG mice are an important asset as a xenotransplantation model for human pancreatic islets or pluripotent stem cell-derived islets. The treatment with the beta cell toxin streptozotocin is the standard procedure for triggering a chemically induced diabetes. Surprisingly, little data has been published about the reproducibility, stress and animal suffering in these NSG mice during diabetes induction. The 3R rules, however, are a constant reminder that existing methods can be further refined to minimize suffering. In this pilot study the dose-response relationship of STZ in male NSG mice was investigated and additionally animal suffering was charted by applying the novel 'Relative Severity Assessment' algorithm. By this we successfully explored an STZ dose that reliably induced diabetes while reduced stress and pain to the animals to a minimum using evidence-based and objective parameters rather than criteria that might be influenced by human bias.
Asunto(s)
Diabetes Mellitus Experimental , Estreptozocina , Animales , Masculino , Ratones , Relación Dosis-Respuesta a Droga , Modelos Animales de Enfermedad , Proyectos Piloto , Humanos , Ratones Endogámicos NOD , Trasplante de Islotes Pancreáticos , Índice de Severidad de la EnfermedadRESUMEN
Wilson's disease (WD) is an autosomal recessive disease that presents mainly with hepatic, neurological, and psychiatric manifestations. Neurological manifestations have been described in the past. Nevertheless, the pathophysiology and the clinical relevance of these manifestations have not been described in great detail in the medical literature. We aim to consolidate the knowledge about the neurological manifestations of WD and present the pathophysiology of each neurological manifestation of the disease. We will give a brief definition, the provenance, and the pathophysiology of the neurological conditions. We collected data from the National Library of Medicine (PubMed) using regular keywords and medical subject headings. Studies were selected applying the following inclusion/exclusion criteria: (1) studies that used exclusively human subjects, (2) papers published in English, and (3) papers from 1990 onward. The exclusion criteria were (1) studies that used animals, (2) papers not published in English, and (3) papers published before 1990. Additional studies were included via reference lists of identified papers and related articles featured in PubMed and Google Scholar. Copper toxicity is the principal factor for brain degeneration seen in WD. Parkinsonism seen in WD has been associated with a nigrostriatal dopaminergic deficit. Resting tremor may have the same pathophysiology as parkinsonism. Action tremor is related to an accumulation of copper in the cerebellum's vermis and hemispheres. At the same time, essential tremor can be explained due to affection of the dentate nucleus. Choreoathetosis is produced due to increased activity of the direct pathway. We did not find specifically associated pathophysiology related to dysarthria. We assume that multiple parts of the brain are involved in that problem. Putamen nucleus damage is the leading cause that explains dystonia seen in WD along with the globus palidus. We did not find a specific localization for seizures in WD, but the pathology seems to be related to decreased levels of B6 and direct toxicity of copper on the brain.
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Babesiosis is a blood-borne disease found mainly in the United States caused by a parasitic piroplasm. While most infections are mild to moderate in immunocompetent hosts, life-threatening complications can occur in those with significant comorbidities like congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD). There is sparse literature discussing the complications of Babesia microti infection or the pathophysiology and management thereof. A literature review was conducted to consolidate the current knowledge about the disease, pathophysiology, and proposed management of all potential complications based on risk factors and other clinical information. A MeSH cross-references strategy was employed in PubMed using the search terms "babesia" and "babesiosis" and the established associated conditions, and the search expanded to increase capture. Only papers written in the English language and discussing human subjects in the North American patient population were included. The initial search yielded 315 papers and, after applying the inclusion/exclusion criteria, a final number of 18 was reviewed. The various complications and pathophysiology thereof are then discussed according to organ system. Babesia is a subversive parasite associated with a variety of conditions. We hope a better appreciation of all potential presentations and complications will help clinicians manage this increasingly common zoonosis and reduce adverse effects. More research is recommended into the pathophysiology and prevention of complications following this and other tick-borne illnesses.
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Neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), and malignant hyperthermia (MH) share similar clinical characteristics. These conditions can present life-threatening situations due to exposure to different drugs. A similar genetic predisposition is suspected between these syndromes as well. This review aims to consolidate the knowledge about the genetics of these disorders and find possible correlations among them to frame the best possible approaches using different drugs without producing life-threatening complications that can be preventable. As a method, we collected data using PubMed with a Medical Subject Headings (MeSH) strategy. The inclusion criteria were as follows: full papers, studies conducted on humans, papers published in the English language, and study types that included case reports, journal articles, multicenter studies, clinical studies, observational studies, or clinical trials. Studies involving animals, articles that were without a visible abstract, study types that included clinical reviews, systematic reviews, or meta-analyses were excluded. 146 papers were reviewed, and 130 papers were removed for no possible extraction of data, duplication of the data, or the study outcome was not compatible with the objective of this review. Ultimately, a total of 17 papers were used for the discussion of this article. As a result of this review, we found no genetic association between NMS, SS, and MH development. Finally, we conclude that NMS, SS, and MH presentation are caused by different mutations which are not associated. 3However, because of the life-threatening clinical presentation of these conditions, genetic tests should be suggested in patients with a family history of these disorders before administering any pertinent drug that increases the risk of developing all these syndromes.
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Stiff-person syndrome (SPS) is a rare and disabling central nervous system disorder with no satisfactory treatment. Muscle rigidity, sporadic muscle spasms, and chronic muscle pain characterize SPS. SPS is strongly correlated with autoimmune diseases, and it is usual to find high titers of antibodies against acid decarboxylase (GAD65). Due to its highly disabling nature and complicated treatment, we aim to create a treatment protocol through a narrative review of currently available treatments that show efficacy. We expect to facilitate management based on treatment responses ranging from first-line medication to refractory medication. We conducted a medical subject heading (MeSH) strategy. We used the term SPS with the subheading treatment: "Stiff-Person Syndrome/Therapy" [MeSH]. An initial data gathering of 270 papers came out with the initial research. After using the inclusion criteria, we had 159 articles. We excluded 31 papers for being either systematic reviews, literature reviews, or meta-analysis. From the 128 remaining articles, we excluded another 104 papers because the extraction of the data was not possible or the study outcome did not meet our demands. There are two main treatments for SPS: GABAergic (gamma-aminobutyric acid) therapy and immunotherapy. For treatment, we suggest starting with benzodiazepines as first-line treatment. We recommend adding levetiracetam or pregabalin if symptoms persist. As second-line therapy, we recommend oral baclofen over rituximab and tacrolimus. We also suggest rituximab over tacrolimus. For patients with refractory treatment, we can use intrathecal baclofen, intravenous immunoglobulin (IVIG), or plasmapheresis. We conclude that intrathecal baclofen and IVIG are more effective than plasmapheresis in patients with refractory symptoms. Propofol may be used as a bridge - temporary therapy before initiating a permanent treatment.
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A new, combined, lidar system has been developed that is able to simultaneously measure profiles of ozone and water vapor onboard aircraft. The concurrent measurement of these complementary trace species in the upper troposphere and lower stratosphere allows inferring exchange processes in the tropopause region. Whereas an advanced H2O differential absorption lidar at 935 nm has successfully been developed and extensively tested at DLR in the past, we describe here an amendment of this lidar by the addition of an ultraviolet (UV) channel to measure ozone. The transmitter of the ozone differential absorption lidar (DIAL) is based on a near-IR optical parametric oscillator that is frequency-converted into the UV spectral range by intracavity sum frequency mixing. Hereby, a continuous UV tuning range of â¼297-317 nm has been achieved. The average output power in this range is higher than 1 W corresponding to more than 10 mJ per pulse at a repetition rate of 100 Hz. The ozone DIAL system has been carefully characterized both on the ground and in flight. The first simultaneously measured two-dimensional cross-sections of ozone and water vapor in the upper troposphere and lower stratosphere have been recorded during the Wave-driven Isentropic Exchange (WISE) field campaign in 2017 demonstrating the high potential of this system for studying exchange processes in this region of the atmosphere.
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The stringent requirements for energy reference measurement represent a challenging task for integrated path differential absorption lidars to measure greenhouse gas columns from satellite or aircraft. The coherence of the lidar transmitter gives rise to speckle effects that have to be considered for accurate monitoring of the energy ratio of outgoing on- and off-line pulses. Detailed investigations have been performed on various measurement concepts potentially suited for deployment within future satellite missions.
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We demonstrate a robust, compact, portable and efficient upconversion detector (UCD) for a differential absorption lidar (DIAL) system designed for range-resolved methane (CH4) atmospheric sensing. The UCD is built on an intracavity pump system that mixes a 1064 nm pump laser with the lidar backscatter signal at 1646 nm in a 25-mm long periodically poled lithium niobate crystal. The upconverted signal at 646 nm is detected by a photomultiplier tube (PMT). The UCD with a noise equivalent power around 127 fW/Hz1/2 outperforms a conventional InGaAs based avalanche photodetector when both are used for DIAL measurements. Using the UCD, CH4 DIAL measurements have been performed yielding differential absorption optical depths with relative errors of less than 11% at ranges between 3 km and 9 km.
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The integrated-path differential-absorption lidar CHARM-F (CO2 and CH4 Remote Monitoring-Flugzeug) was developed for the simultaneous measurement of the greenhouse gases CO2 and CH4 onboard the German research aircraft HALO (High Altitude and Long Range Research Aircraft). The purpose is to derive the weighted, column-averaged dry-air mixing ratios of the two gases with high precision and accuracy between aircraft and ground or cloud tops. This paper presents the first measurements, performed in the spring of 2015, and shows performance analyses as well as the methodology for the quantification of strong point sources applied on example cases. A measurement precision of below 0.5% for 20 km averages was found. However, individual measurements still show deviations of the absolute mixing ratios compared to corresponding data from in situ profiles. The detailed analysis of the methane point source emission rate yields plausible results (26±3 m3/min or 9.2±1.15 kt CH4 yr-1), which is in good agreement with reported numbers. In terms of CO2, a power plant emission could be identified and analyzed.
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Trade-wind cumuli constitute the cloud type with the highest frequency of occurrence on Earth, and it has been shown that their sensitivity to changing environmental conditions will critically influence the magnitude and pace of future global warming. Research over the last decade has pointed out the importance of the interplay between clouds, convection and circulation in controling this sensitivity. Numerical models represent this interplay in diverse ways, which translates into different responses of trade-cumuli to climate perturbations. Climate models predict that the area covered by shallow cumuli at cloud base is very sensitive to changes in environmental conditions, while process models suggest the opposite. To understand and resolve this contradiction, we propose to organize a field campaign aimed at quantifying the physical properties of trade-cumuli (e.g., cloud fraction and water content) as a function of the large-scale environment. Beyond a better understanding of clouds-circulation coupling processes, the campaign will provide a reference data set that may be used as a benchmark for advancing the modelling and the satellite remote sensing of clouds and circulation. It will also be an opportunity for complementary investigations such as evaluating model convective parameterizations or studying the role of ocean mesoscale eddies in air-sea interactions and convective organization.
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A high-performance airborne UV Rayleigh lidar system was developed within the European project DELICAT. With its forward-pointing architecture, it aims at demonstrating a novel detection scheme for clear air turbulence (CAT) for an aeronautics safety application. Due to its occurrence in clear and clean air at high altitudes (aviation cruise flight level), this type of turbulence evades microwave radar techniques and in most cases coherent Doppler lidar techniques. The present lidar detection technique relies on air density fluctuation measurement and is thus independent of backscatter from hydrometeors and aerosol particles. The subtle air density fluctuations caused by the turbulent air flow demand exceptionally high stability of the setup and in particular of the detection system. This paper describes an airborne test system for the purpose of demonstrating this technology and turbulence detection method: a high-power UV Rayleigh lidar system is installed on a research aircraft in a forward-looking configuration for use in cruise flight altitudes. Flight test measurements demonstrate this unique lidar system being able to resolve air density fluctuations occurring in light-to-moderate CAT at 5 km or moderate CAT at 10 km distance. A scaling of the determined stability and noise characteristics shows that such performance is adequate for an application in commercial air transport.
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For the first time an upconversion based detection scheme is demonstrated for lidar measurements of atmospheric CO2-concentrations, with a hard target at a range of 3 km and atmospheric backscatter from a range of ~450 m. The pulsed signals at 1572 nm are upconverted to 635 nm, and detected by a photomultiplier tube, to test how the upconversion technology performs in a long range detection system. The upconversion approach is compared to an existing direct detection scheme using a near-IR detector with respect to signal-to-noise ratio and quantum efficiency. It is for the first time analyzed how the field-of-view of a receiver system, for long range detection, depends critically on the parameters for the nonlinear up-conversion process, and how to optimize these parameters in future systems.
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The influence of molecular scattering models on aerosol optical properties measured by high spectral resolution lidar (HSRL) is experimentally investigated and theoretically evaluated. The measurements analyzed in this study were made during three field campaigns by the German Aerospace Center airborne HSRL. The influence of the respective theoretical model on spaceborne HSRL retrievals is also estimated. Generally, the influence on aerosol extinction coefficient can be neglected for both airborne and spaceborne HSRLs. However, the influence on aerosol backscatter coefficient depends on aerosol concentration and is larger than 3% (6%) at ground level for airborne (spaceborne) HSRLs, which is considerable for the spaceborne HSRL, especially when the aerosol concentration is low. A comparison of the HSRL measurements and coordinated ground-based sunphotometer measurements shows that the influence of the model is observable and comparable to the measurement error of the lidar system.
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An airborne high spectral resolution lidar (HSRL) based on an iodine absorption filter and a high-power frequency-doubled Nd:YAG laser has been developed to measure backscatter and extinction coefficients of aerosols and clouds. The instrument was operated aboard the Falcon 20 research aircraft of the German Aerospace Center (DLR) during the Saharan Mineral Dust Experiment in May-June 2006 to measure optical properties of Saharan dust. A detailed description of the lidar system, the analysis of its data products, and measurements of backscatter and extinction coefficients of Saharan dust are presented. The system errors are discussed and airborne HSRL results are compared to ground-based Raman lidar and sunphotometer measurements.